Figure 2.

Models of inflammasome activation. Coordination of a manifold series of signals culminates in the activation of the inflammasome. Three models have been put forth to explain mechanisms of inflammasome activation. The observation that inflammasomes are activated by a diverse array of biological molecules suggests an indirect mechanism of sensing as opposed to a direct interaction with a receptor ligand pair. Reactive oxygen species (ROS) are induced by many of the known activators of inflammasomes. It is postulated that the generation of ROS, possibly via the phagosomal NADH-oxidase, releases thioredoxin-interacting protein (TXNIP) from thioredoxin (TRX). TXNIP, which is free from TRX, can bind to NLRP3, possibly by competing with HSP90 and SGT1, which retain NLRP3 in an inactive state. The NLRP3 TXNIP complex facilitates inflammasome formation through an unknown mechanism that might relate to the activity of superoxide dismutase (SOD1). Alternatively, the release of cathepsin B (and possibly other cathepsins) due to lysosomal destabilization activates the inflammasome during phagocytosis. How cathepsin B activates the inflammasome is currently unknown, but activation requires its enzymatic activity. The final model posits pore formation at the plasma membrane that allows for K⁺ efflux. Pore formation can occur via the P2X7 receptor/pannexin-1 oligo-structure via pathogen toxins or ion channels. A modification to the last model suggests that small PAMPs can gain cytosolic access via the P2X7 receptor/pannexin-1 hemichannel and activate the inflammasome.